Skip Navigation

Changes in Plasma Human Immunodeficiency Virus Type 1 RNA Associated with Herpes Simplex Virus Reactivation and Suppression

  1. Timothy Schacker1,
  2. Judith Zeh3,4,
  3. Huilin Hu4,a,
  4. Mary Shaughnessy6 and
  5. Lawrence Corey2,3,5,6
  1. 1Department of Medicine, University of Minnesota, Minneapolis; Departments of
  2. 2Medicine,
  3. 3Laboratory Medicine,
  4. 4Statistics, and
  5. 5Microbiology, University of Washington, and
  6. 6Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle
  1. Reprints and correspondence: Dr. Timothy Schacker, Dept. of Medicine, University of Minnesota, Box 250, 516 Delaware St. SE, Minneapolis, MN 55455 (Schac008{at}tc.umn.edu)
 
Next Section

Abstract

In early trials of antiretroviral therapy, acyclovir was associated with increased survival by an unknown mechanism. The hypothesis that subclinical herpes simplex virus (HSV) reactivation was associated, in vivo, with increased plasma human immunodeficiency virus (HIV) RNA and suppression with a reduced plasma HIV RNA load was investigated. HSV cultures were performed daily on HSV-2–positive/HIV-positive patients, and plasma HIV-1 RNA loads were measured at regular intervals. A subset of patients prior to, during, and after HSV suppression with high-dose acyclovir was measured to determine whether HSV suppression was associated with a decrease in HIV replication. Most (25/27 HSV-2–positive/HIV-positive persons) reactivated HSV. Total HSV shedding rate was strongly correlated with plasma HIV-1 RNA load (R=0.54; P=.004), and the plasma HIV-1 RNA level at a given CD4 cell count was 48% lower when treated with acyclovir. These data indicate that frequent mucosal HSV reactivation influences HIV replication in vivo and daily HSV suppression may be important in the management of HSV-positive/HIV-positive persons

Herpes simplex virus (HSV) is a significant pathogen in persons infected with human immunodeficiency virus (HIV). It was one of the first opportunistic infections affecting immunocompromised homosexual men [1]. Seroepidemiologic studies have established that HSV is among the most common viral infections in persons with HIV-1 infection [2 –8]. Over 60% of persons who are at risk for HIV-1 are HSV-2 seropositive, including men who have sex with men and injection drug users [9 –12]. It has recently been shown that, in developing countries, HSV-2 infection is even more prevalent than in the United States or Europe. Among adults >30 years old, rates of HSV-2 infection in the Central African Republic, Tanzania, South Africa, Zambia, Kenya, Uganda, and Zimbabwe are 82%, 60%, 82%, and 74%, respectively [2, 13 –16]

The role that HSV-2 infection plays in HIV disease progression is still controversial. Several studies have demonstrated that high doses of acyclovir (3.2 g/day), when administered in combination with zidovudine, provided a survival benefit for persons who were randomized to receive acyclovir [17, 18]. The mechanism for this reduction in mortality was unclear, with many authorities feeling that this was related to acyclovir’s action on reducing cytomegalovirus (CMV) reactivation [19]. However, a retrospective survey of acyclovir use suggested lower doses, which were effective only against α-herpes viruses such as varicella-zoster virus (VZV) and HSV, were also associated with a survival benefit [20], and a recent meta-analysis found that 7 of 8 studies showed a survival benefit for HIV infected persons receiving acyclovir. Overall, the odds ratio (OR) for acyclovir treatment reducing mortality was 0.78 (95% confidence interval [CI], 0.65–0.93) [21]. Acyclovir has no effect on HIV replication [22]. The decreased mortality associated with its use may be through its suppression of replication of the α-herpes viruses, HSV-1, HSV-2, and VZV

A suggested mechanism for suppression affecting HIV survival is a direct effect of specific HSV proteins on genes regulating the rate of HIV-1 replication [23]. In vitro, the HSV immediate early gene coding for ICPO and ICP27 HSV have been shown to transactivate the long-terminal repeat portion of the HIV genome [24 –26], and coinfection of MT-4 cells with HSV and HIV can lead to increased replication of HIV [27, 28]. An in vivo demonstration of this phenomenon may be the observation that keratinocytes, observed to be coinfected with both HSV-1 and HIV, show increased numbers of HIV virions, compared with those cells infected only with HIV [29]. Our group has demonstrated the presence of high titers of HIV-1 virions in mucosal HSV-2 infection and that mucosal variants may subsequently appear in plasma [30]. These data suggest that frequent HSV reactivation may influence the replicating pool of HIV-1 and influence disease progression

One of the concerns that has arisen about the importance of HSV reactivation as a factor in HIV-1 disease pathogenesis is the relatively low frequency of clinical expression of HSV in the HIV-positive subjects [31]. However, we have recently shown that, when samples are collected daily, HSV-2 may be cultured on 5%–10% of days in immunocompetent persons and HSV DNA detected on >20% of days [32, 33]. Among HIV-1–infected persons studied, HSV can be detected on 10% of days by culture and on up to 40%–50% of days using HSV polymerase chain reaction (PCR) [34-36]. Given the seroepidemiologic studies suggesting HSV is a nearly universal pathogen among HIV-1 infected persons and the in vitro and in vivo data suggesting a significant interaction between these 2 pathogens that may impact the natural history of HIV infection, we wanted to examine the association between clinical and subclinical HSV reactivation and HIV-1 RNA levels in plasma and determine if suppression of HSV alters plasma HIV-1 RNA levels

Previous SectionNext Section

Methods

Patient Selection

HSV seropositive HIV-infected persons were recruited into these protocols between 1994 and 1996. Eligibility criteria included serum antibodies to HSV-2 or both HSV-1 and -2, demonstrated by Western blot, age >18 years, detectable HIV-1 RNA in plasma at entry, and no history of anti-HSV therapy or changes in antiretroviral therapy within 2 weeks of study entry. There were no restrictions because of sex, race, or stage of HIV-1 infection. All patients were monitored at the University of Washington Virology Research Clinic, Seattle. At entry, each subject completed a standardized interview to record history of prior HSV recurrences and frequency and type of past antiviral therapy for both HSV and HIV-1

Protocol Descriptions

Study 1: Assessment of plasma HIV-1 RNA during and between sequential HSV reactivations.This protocol involved monthly visits to the clinic for routine medical and genital examinations. Blood samples to measure CD4 T cell count and plasma HIV-1 RNA loads were collected at each visit. Patients were given information about the typical signs and symptoms of HSV recurrences and asked to return to the clinic after each HSV recurrence, at which time they would be monitored at every-other-day intervals with genital exams and cultures for HSV. Plasma for HIV-1 RNA levels was also drawn on each clinic visit of the recurrence. After the lesions had healed, the patient resumed monthly evaluations until the next HSV reactivation. Daily cultures for HSV were collected from external genital, perirectal, and oropharyngeal sites for each patient during the study period

Study 2: Assessment of plasma HIV-1 RNA before, during, and after suppressive therapy with acyclovir.This evaluation measured plasma HIV-1 RNA loads in patients weekly for 8 weeks while not taking acyclovir, then weekly for 8 weeks while taking daily suppressive acyclovir (800 mg orally, 3 times/day), and then weekly for an additional 8 weeks while not taking acyclovir. The 800 mg dose of acyclovir was chosen to achieve maximal levels of suppression of subclinical HSV-2 reactivation. Patients obtained daily HSV cultures, as described below, for the 24-week study period. If the patient experienced a recurrence during follow-up, they were instructed to return to clinic for examination of the lesions. All patients were asked to refrain from initiating therapy for an HSV outbreak. Data collected from Study 2 patients who were not taking suppressive acyclovir were included in Study 1 analyses

Collection of Daily Home HSV Cultures

Methods utilized in the daily collection of swabs at home have been described elsewhere [34 –37]. Each person collected 4 specimens daily, 1 sample from each of 4 anatomic sites, using separate Dacron swabs for each culture. Men swabbed the oropharynx, penile shaft, urethra, and rectum; women swabbed the oropharynx, external vaginal labia, vaginal/cervical area, and rectum. Participants were instructed to obtain the cultures at the same time each day, preferably upon awakening. Oral/pharyngeal cultures were obtained by inserting a Dacron swab into the mouth and vigorously rubbing it along the gum line and over the palate. Urethral cultures were obtained from men by rubbing a Dacron swab over the urethral meatus. Penile skin cultures were obtained by rubbing a Dacron swab along the entire ventral and dorsal shaft of the penis. Rectal cultures were obtained by inserting a swab ∼2–4 cm into the anus and gently rotating it. Each Dacron swab was placed into a separate vial containing viral transport media and stored in the refrigerator. Cultures were picked up by a courier within 36 h of collection and transported to the virology laboratory of the University of Washington and immediately set up in tissue culture. Subjects also filled out a daily diary card that recorded site-specific presence or absence of symptoms (pain, tingling, numbness, or itching) and/or presence of lesions [32]. All diary cards were collected monthly and reviewed by the study clinician

Laboratory Studies

Serologic assays and T cell analysis.HIV-1 seropositivity was confirmed by EIA and Western blot. Serologic testing for HSV antibodies was performed on entry serum by Western blot analysis [2]. CMV seropositivity was determined by EIA. CD4 subset analysis was done by the hematopathology laboratory of the University of Washington, which is certified by the AIDS Clinical Trials Group for this assay

HSV culture.HSV isolation was performed as described elsewhere [34 –37]

HIV-1 load.Plasma HIV-1 RNA load was determined using the initial bDNA assay (Chiron), which has a lower limit of detection of 10,000 HIV-1 RNA copies/mL plasma [38]. When the Chiron ultrasensitive method became available (lower limit of detection of 50 HIV-1 copies/mL plasma), plasma samples that had <12,000 HIV-1 RNA copies/mL in the initial assay were retested by the ultrasensitive assay

CMV PCR.CMV PCR was performed on plasma samples collected from all patients during follow-up in the suppression substudy to ensure that changes in plasma HIV-1 RNA levels were not attributable to CMV reactivation. The CMV PCR assay was able to detect at least 200 copies of CMV DNA/mL of plasma [39]

Study Endpoints and Definitions of Terms

We used the term “shedding” to indicate isolation of virus by culture, regardless of the presence of genital signs and symptoms. “Total HSV shedding rate” is defined as the percentage of days when cultures were obtained on which HSV-1 and/or HSV-2 was isolated. “Subclinical HSV shedding rate” is defined as the percentage of days cultures that were obtained on which HSV-1 and/or HSV-2 was isolated and no lesion was present. “Clinical HSV shedding rate” is defined as the percentage of days cultures were obtained on which HSV-1 and/or HSV-2 was isolated and a lesion was present. Thus the sum of clinical and subclinical shedding rates is the total shedding rate. “Recurrence” indicates the presence of a lesion on consecutive days at any site; “reactivation” indicates either a recurrence or shedding

Statistical Analysis

Both exploratory and statistical modeling techniques were used to evaluate the interrelationship between HSV reactivation and plasma HIV-1 RNA levels. Initially, box plots and scatterplots were used to examine relationships between plasma HIV RNA levels and possible predictors. Regression models, with log10 HIV RNA load for a given person on a given day as the response variable, were then formulated to compare HIV RNA levels during and between clinical HSV episodes with on-versus-off acyclovir suppression. Jackknife estimates [40] of standard errors of regression coefficients were used, as plasma HIV-1 RNA measurements for the same individual at different times were expected to correlated with each other. When the independence assumption is violated, the estimated coefficients from a regression are still unbiased, but the usual estimates of standard error may be misleading. The jackknife technique consists of deleting individual patients (not individual observations) from the data one by one, refitting the regression model and using the set of leave-one-out parameter estimates to calculate standard errors. The jackknife estimates of standard error are asymptotically equivalent to other robust estimates [40]. Even when there are correlations among HIV RNA values for an individual, the jackknife will produce a correct estimate of the standard error of the estimated coefficients. The jackknife estimates of standard error are used to calculate Student’s t test statistics and obtain P values for the regression coefficients. All reported P values are 2-sided

Previous SectionNext Section

Results

Study population.Twenty-seven patients (24 men and 3 women) were recruited for Study 1. Of these, 12 participated in Study 2. Demographic characteristics of the cohort are described in table 1 and reflect the epidemiology of HIV-1 disease in Seattle at the time this study was completed. All 27 participants had antibodies to HSV-2, and 19 (70%) of 27 had antibodies to both HSV-1 and HSV-2, with 85% reporting a history of anogenital HSV and 44% reporting a history of oral/labial HSV. As this study was completed prior to the introduction of highly active antiretroviral therapy (HAART), only 10 persons were receiving antiretroviral therapy (ART) during follow-up (usually monotherapy) (table 1)

Figure 1
View larger version:
Figure 1

Human immunodeficiency virus (HIV) RNA is plotted versus percentage of days with positive herpes simplex virus (HSV) culture. This demonstrates a highly significant relationship between plasma HIV RNA load and total HSV shedding rate (r=0.54; P=.004), suggesting that HSV reactivation may be an important factor in regulating HIV replication

Figure 2
View larger version:
Figure 2

Geometric mean human immunodeficiency virus (HIV) RNA over 2-week periods for each of the 12 suppression substudy participants. Dashed lines connect the means for a given participant, and the solid line gives the geometric mean over participants for each 2-week period. The weeks during suppressive acyclovir therapy are shaded

Table 1
View larger version:
Table 1

Baseline characteristics among the 27 patients followed with daily swabbing during and between clinical episodes of herpes simplex virus (HSV)–2 (Study 1) and the subset of 12 patients who received acyclovir suppression (Study 2)

HSV reactivation during follow-up.Patients were monitored a median of 5 months (range, 1–14 months) and completed a total of 4339 days of follow-up (table 2), during which time 10,701 HSV cultures and 865 HIV RNA assays were performed. HSV-2 was isolated at least once during follow-up from 23 (85%) of 27 patients. Of the 19 patients with antibodies to both HSV-1 and HSV-2, 15 experienced both HSV-1 and HSV-2 shedding and 3 experienced only HSV-2 shedding. Of the 4 patients who did not have a positive HSV culture during follow-up, only 2 reported lesions consistent with HSV. Patients were monitored a median of 87 days with no anti-HSV therapy. Although lesions were present on a median of 21.8% of these days, the median total HSV shedding rate was 12.8%, indicating that lesions healed slowly in many subjects (table 3)

Table 2
View larger version:
Table 2

Herpes simplex virus (HSV) reactivation among all 27 patients during both studies

Table 3
View larger version:
Table 3

Summary statistics for percentage of days with herpes simplex virus reactivation for both studies

Lesions were noted on 60% of days on which HSV was isolated; thus, 40% of days from which HSV was isolated were associated with subclinical shedding (table 2). On the days that lesions were reported, HSV-1 was isolated on 9 days, HSV-2 on 257 days, and both HSV-1 and HSV-2 were isolated on 8 days. On the days that the HSV culture was positive and no lesions were reported (subclinical shedding), HSV-1 was isolated on 39 days, HSV-2 on 136 days, and both HSV-1 and HSV-2 were isolated on 4 days. Of the 60 cultures testing positive for HSV-1, 52 were oral and 8 were rectal. All but 3 cultures testing positive for HSV-2 were nonoral. Thus, anogenital HSV-2 shedding dominated the clinically observed and subclinically documented reactivation rates we calculated

Study 1: Association between plasma HIV-1 RNA and HSV reactivation.Initial examinations of relationships between HSV reactivation, HIV-1 RNA loads, and CD4 cell count were on the basis of summary statistics computed for each of the 27 patients. The geometric mean plasma HIV-1 RNA tended to be greater in patients whose mean CD4 cell count was lower, but the correlation was not significant (R=-0.35; P=.072). As expected, based on earlier work, we found a significant negative correlation between the mean CD4 cell count and the overall HSV shedding rate (R=-0.48; P=.01) [34]. The median total HSV shedding rates for persons with entry CD4 cell counts of <200, 200–500, and >500 cells/mm3 were 31%, 15%, and 6%, respectively

The results of Mole et al. [41] led us to expect higher geometric mean plasma HIV-1 RNA levels in subjects with higher percentages of days with lesions, but we found no significant positive correlation (R=0.34; P=.083). The median plasma HIV-1 RNA levels when lesions were present was 24,800 copies/mL, compared with 24,400 copies/mL when lesions were absent (table 4). However, the total HSV shedding rate, which measures the percentage of time that HSV was proven to be present by culture, had a strong positive correlation with geometric mean plasma HIV-1 RNA load (figure 1; R=0.54; P=.004). These data suggest that subclinical HSV shedding significantly influenced the association between HSV reactivation and plasma HIV-1 RNA levels

Table 4
View larger version:
Table 4

Plasma human immunodeficiency virus (HIV) RNA levels during vs. between herpes simplex virus (HSV) lesions for all 27 patients who collected daily swabs during and between clinical episodes of HSV-2 in Study 1 and while taking daily suppressive doses of acyclovir vs. not taking daily suppressive doses of acyclovir

We used multiple regression analysis to account for possible confounders such as CD4 cell count. In our 27 subjects, the median CD4 cell count at entry was 333 cells/mm3 (range, 4–921 cells/mm3), whereas, in the study by Mole et al. [41], the median CD4 cell count was 45 cells/mm3 with a much narrower range (4–336 cells/mm3). As such, we performed an analysis in which adjustment for CD4 cell count was made to define whether clinical HSV reactivation influenced plasma HIV-1 RNA level. Using presence of a lesion and CD4 cell count as predictors of plasma HIV-1 RNA level, plasma HIV-1 RNA level at a given CD4 cell count was estimated to be 32% lower in the absence of a lesion, compared with when a lesion was present (P=.032). Thus, in this adjusted analysis, we did find a significant direct relationship between clinical HSV reactivation and plasma HIV-1 RNA loads

Study 2: Reduction in plasma HIV-1 RNA load while experiencing acyclovir suppression.Twelve subjects (11 men and 1 woman) who were HIV-1 and HSV-2 seropositive were recruited to participate in the acyclovir suppression study. Cultures were obtained on a median of 59 days (range, 27–75 days) after the start of acyclovir therapy and a median of 78 days (range, 58–108) after not receiving acyclovir. As expected, oral acyclovir was very successful in reducing both recurrences and HSV shedding in these patients. All patients reported recurrences, and all but one had positive HSV cultures during the substudy when no acyclovir suppression was being taken. While receiving suppressive acyclovir, 8 reported lesions, but only 3 had positive cultures. While receiving acyclovir, the median percentage of days with lesions was reduced from 32.1% to 3.4%, and the median total HSV shedding rate was reduced from 19.3% to 0 (table 3)

Daily acyclovir therapy was associated with reduction in plasma HIV-1 RNA loads (figure 2; table 4). All 12 patients experienced a reduction during suppressive therapy. Median plasma HIV-1 RNA level decreased by 5100 copies/mL. Multiple regression determined that both acyclovir suppression and high CD4 cell count significantly reduced plasma HIV-1 RNA levels (P=.035 and P=.028, respectively). Plasma HIV-1 RNA level at a given CD4 value on suppressive therapy was estimated to be 48% lower than while not receiving suppressive therapy

Effect of CMV reactivation on plasma HIV-1 RNA load.To determine whether the effect of acyclovir suppression on plasma HIV-1 RNA was because of its effect on reduction of CMV reactivation, we confirmed that all 12 subjects were CMV antibody positive, and all available plasma samples (320/380) from these patients were subjected to CMV DNA PCR testing. The remaining 60 samples were either unavailable or of insufficient volume to allow for CMV DNA PCR. The available samples represented a median of 29 per patient (range, 5–47 samples). Overall, CMV was detected in 19 samples from 9 patients during follow-up. We detected no relationship between HIV levels in plasma and CMV reactivation in either univariate or multivariate analyses, and inclusion of CMV shedding did not alter the relationship between HSV reactivation and plasma HIV load

Previous SectionNext Section

Discussion

These data indicate that frequent mucosal HSV reactivation is associated with higher levels of plasma HIV-1 RNA and that suppression of HSV is associated with a measurable decrease in plasma HIV-1 RNA levels. Our current conclusions are based on analysis of samples collected daily. Almost all other trials evaluating the association between HSV and HIV have used clinical observation to define HSV reactivation and not culture data that confirm HSV reactivation and measure subclinical expression of the virus [17, 18, 20, 41]. In our previous studies, we have shown that much of the HSV reactivation among HIV-infected persons, especially those with higher CD4 T cell counts, is subclinical [34 –36], indicating the need for objective daily sampling to define the rate of HSV reactivation. We followed 27 patients with daily viral cultures of the mouth, genitals, and rectum and frequent plasma HIV-1 RNA measurements, which allowed us to show a correlation between HSV shedding rate and HIV-1 RNA load, as well as to analyze individual patient differences in plasma HIV-1 RNA levels between days with and without HSV lesions. Our studies were designed to define the role of subclinical and clinical HSV reactivation in HIV-1 replication and (Study 2) determine whether HSV suppression could reduce HIV replication in vivo

Our data indicate that HSV reactivation (including HSV-1 but predominantly HSV-2 in these patients) markedly influences HIV plasma viremia. Suppression of HSV with acyclovir was associated with a reduction in plasma HIV RNA. Because 40% of HSV shedding was subclinical and acyclovir was even more effective in reducing HSV shedding than in reducing lesions, our results suggest that subclinical as well as clinical HSV reactivation influences plasma HIV RNA. Of note, 10 Study 2 patients experienced subclinical shedding before and after the period when acyclovir was given, but only 3 showed shedding during suppression. The reduction in median plasma HIV-1 RNA load was >5000 copies/mL. Although our study was not designed to define the duration in which acyclovir could reduce plasma HIV-1 RNA levels, if one extrapolates the level of HIV-1 RNA suppression over time, it approaches those that are associated with a measurable survival benefit [42] and would account for the reduced hazard ratio for acyclovir seen in meta-analyses [21]. Our data thus provide some biological understanding beyond the clinical studies indicating a survival benefit on acyclovir among patients on monotherapy and double combination therapy [17 –21]

Daily acyclovir therapy has not been embraced by most HIV care providers and has not been recommended by the recent Centers for Disease Control and Prevention Guidelines [43], which do not even recommend serologic testing for HSV-2 among HIV positive persons. Our data indicate this inattention to HSV-2 reactivation should be reevaluated. Frequent HSV reactivation influences HIV-1 plasma RNA levels, and our data indicate this occurs with sufficient regularity to quantitatively affect plasma HIV-1 levels in vivo. One intriguing aspect of our data is that they may provide an explanation for the fluctuations that people have recorded in HIV-1 RNA levels on and off therapy [42, 44]. These “blips” may not be measurement errors in the plasma HIV-1 RNA assays, but may be related to true in vivo “microblasts” of HIV-1 replication associated with HSV reactivation. As HSV shedding rates are higher in persons with low CD4 T cell counts, the addition of acyclovir to “salvage therapy” should be studied

This study was conducted prior to the introduction of HAART, and patients receiving ART were receiving single and double agent regimens of nucleoside analogues not typically associated with complete suppression of HIV replication. Introduction of HAART has resulted in a significant decrease in AIDS-related morbidity and mortality [44]. It is unknown whether patients receiving HAART have fewer episodes of clinical or subclinical HSV shedding than HIV-positive patients not receiving HAART, or who have failed therapy with increasing plasma levels of HIV-1 RNA. In addition, these studies are primarily in men, and there are reported sex differences in the rate of HSV reactivation [45]. How these data may extend to HIV-1–infected women is unknown. Moreover, many persons receiving HAART have bursts of HIV replication, and whether HSV reactivations are associated with such bursts is unknown. Our study suggests such issues should be examined

In summary, our data have several clinical implications for the management of HIV-infected persons. Because HSV-2 reactivation, especially frequent reactivation, influences HIV replication, testing for HSV specific antibodies should be considered for HIV-infected persons, even if they do not report a history of HSV infection. Second, defining the frequency of HSV reactivation, especially among those who are not on effective antiretroviral therapy and those who have low CD4 T cell counts, appears to be warranted. Further studies in women, patients shedding predominantly HSV-1, and those receiving HAART appear warranted to evaluate the role HSV plays in plasma HIV RNA load elevation or HIV-1 transmission, and whether acyclovir suppression offers benefit to such persons

Previous SectionNext Section

Acknowledgments

We thank Stacy Selke for data management, Nancy Coomer for manuscript preparation, Eric Peterson and the staff of the University of Washington Retrovirology Laboratory, and the University of Washington Virology Laboratory under the direction of Rhoda Ashley and Anne Cent. In addition, we thank Anna Wald for her careful review of the manuscript

Previous SectionNext Section

Footnotes

  • ↵The institutional review board of the University of Washington approved this study

    Financial support: National Institutes of Health (grants AI30731 and AI01338) and the AIDS Clinical Trial Group (grant 2-U01-A127664-06)

  • ↵Present affiliation: Novartis Pharmaceuticals, East Hanover, New Jersey

  • Received May 8, 2002.
  • Revision received August 12, 2002.
Previous Section
 

References

  1. 1.↵
    1. Siegal FP,
    2. Lopez C,
    3. Hammer GS,
    4. et al
    . Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981;305:1439-44.
    MedlineWeb of Science
  2. 2.↵
    1. Ashley R,
    2. Wald A
    . Genital herpes: review of the epidemic and potential use of type‐specific serology. Clin Microbiol Rev 1999;12:1-8.
    Abstract/FREE Full Text
  3. 3.↵
    1. McFarland W,
    2. Gwanzura L,
    3. Bassett MT,
    4. et al
    . Prevalence and incidence of herpes simplex virus type 2 infection among male Zimbabwean factory workers. J Infect Dis 1999;180:1459-65.
    Abstract/FREE Full Text
  4. 4.↵
    1. Obasi A,
    2. Mosha F,
    3. Quigley M,
    4. et al
    . Antibody to herpes simplex virus type 2 as a marker of sexual risk behavior in rural Tanzania. J Infect Dis 1999;179:16-24.
    Abstract/FREE Full Text
  5. 5.↵
    1. Langeland N,
    2. Haarr L,
    3. Mhalu F
    . Prevalence of HSV‐2 antibodies among STD clinic patients in Tanzania. Int J STD AIDS 1998;9:104-7.
    Abstract/FREE Full Text
  6. 6.↵
    1. Wooley PD,
    2. Chandiok S,
    3. Pumphrey J,
    4. et al
    . Serological prevalence of herpes simplex virus type 2 amongst GUM clinic attendees in a district general hospital setting. Int J STD AIDS 2000;11:379-82.
    Abstract/FREE Full Text
  7. 7.↵
    1. Boulos R,
    2. Ruff AJ,
    3. Nahmias A,
    4. et al
    . Herpes simplex virus type 2 infection, syphilis, and hepatitis B virus infection in Haitian women with human immunodeficiency virus type 1 and human T lymphotropic virus type 1 infections. J Infect Dis 1992;166:418-20.
    Abstract/FREE Full Text
  8. 8.↵
    1. Auvert B,
    2. Ballard R,
    3. Campbell C,
    4. et al
    . HIV infection among youth in a South African mining town is associated with herpes simplex virus–2 seropositivity and sexual behaviour. AIDS 2001;15:885-98.
    CrossRefMedlineWeb of Science
  9. 9.↵
    1. Stamm WE,
    2. Handsfield HH,
    3. Rompalo AM,
    4. Ashley RL,
    5. Roberts PL,
    6. Corey L
    . The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA 1988;260:1429-33.
    Abstract/FREE Full Text
  10. 10.↵
    1. Hook E,
    2. Cannon R,
    3. Nahmias A,
    4. et al
    . Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. J Infect Dis 1992;165:251-55.
    Abstract/FREE Full Text
  11. 11.↵
    1. Holmberg S,
    2. Gerber A,
    3. Steward J,
    4. Byers R,
    5. Nahmias A
    . Herpes simplex virus type 2 and HIV seroconversion. J Acquir Immune Defic Syndr 1991;4:732-4.
    MedlineWeb of Science
  12. 12.↵
    1. Tabet SR,
    2. Krone MR,
    3. Paradise MA,
    4. Corey L,
    5. Stamm WE,
    6. Celum CL
    . Incidence of HIV and sexually transmitted diseases (STD) in a cohort of HIV‐negative men who have sex with men (MDM). AIDS 1998;12:2041-8.
    CrossRefMedlineWeb of Science
  13. 13.↵
    1. Chen C,
    2. Ballard R,
    3. Beck‐Sague C,
    4. et al
    . Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection. Sex Transm Dis 2000;27:21-29.
    MedlineWeb of Science
  14. 14.↵
    1. Weiss HA,
    2. Buve A,
    3. Robinson NJ,
    4. et al
    . The epidemiology of HSV‐2 infection and its association with HIV infection in four urban African populations. AIDS 2001;15:S97-S108.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Greenblatt RM,
    2. Lukehart SA,
    3. Plummer FA,
    4. et al
    . Genital ulceration as a risk factor for human immunodeficiency virus infection. AIDS 1988;2:47-50.
    MedlineWeb of Science
  16. 16.↵
    1. Mbopi‐Keou FX,
    2. Gresenguet G,
    3. Mayaud P,
    4. et al
    . Genital herpes simplex virus type 2 shedding is increased in HIV‐infected women in Africa. AIDS 1999;13:536-37.
    CrossRefMedlineWeb of Science
  17. 17.↵
    1. Youle MS,
    2. Gazzard BG,
    3. Johnson MA,
    4. et al
    . Effects of high‐dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double‐blind, placebo‐controlled study. AIDS 1994;8:641-9.
    MedlineWeb of Science
  18. 18.↵
    1. Cooper DA,
    2. Pehrson O,
    3. Pedersen C,
    4. et al
    . The efficacy and safety of zidovudine alone or as cotherapy with acyclovir for the treatment of patients with AIDS and AIDS‐related complex: a double‐blind, randomized trial. AIDS 1993;7:197-207.
    MedlineWeb of Science
  19. 19.↵
    1. Gluckman E,
    2. Lotsberg J,
    3. Devergie A,
    4. et al
    . Prophylaxis of herpes infections after bone marrow transplantation by oral acyclovir. Lancet 1983;2:706-8.
    MedlineWeb of Science
  20. 20.↵
    1. Stein DS,
    2. Graham NMH,
    3. Park LP,
    4. et al
    . The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival in the Multicenter AIDS Cohort Study. Ann Intern Med 1994;121:100-8.
    Abstract/FREE Full Text
  21. 21.↵
    1. Ioannidis J,
    2. Collier A,
    3. Cooper D,
    4. et al
    . Clinical efficacy of high‐dose acyclovir in human immunodeficiency virus infection: a meta‐analysis of randomized individual patient data. J Infect Dis 1998;178:349-59.
    Abstract/FREE Full Text
  22. 22.↵
    1. Collier AC,
    2. Schoenfeld D,
    3. Hirsch M,
    4. et al
    . Lack of effect on survival of high dose acyclovir and zidovudine compared with zidovudine alone for acquired immunodeficiency syndrome. Antiviral Ther 1998;3:25-32.
    MedlineWeb of Science
  23. 23.↵
    1. Mosca J,
    2. Bednarik D,
    3. Raj N,
    4. et al
    . Herpes simplex virus type 1 can reactivate transcription of latent human immunodeficiency virus. Nature 1987;325:67-70.
    CrossRefMedline
  24. 24.↵
    1. Schafer S,
    2. Vlach J,
    3. Pitha P
    . Cooperation between herpes simplex virus type 1‐encoded ICPO and tat to support transcription of human immunodeficiency virus type 1 long terminal repeat in vivo can occur in absence of the TAR binding site. J Virol 1996;70:6937-46.
    Abstract/FREE Full Text
  25. 25.↵
    1. Margolis D,
    2. Rabson A,
    3. Straus S,
    4. Ostrove J
    . Transactivation of the HIV‐1 LTR by HSV‐1 immediate‐early genes. Virology 1992;186:788-91.
    CrossRefMedlineWeb of Science
  26. 26.↵
    1. Diaz JJ,
    2. Dodon MD,
    3. Schaerer‐Uthurralt N,
    4. et al
    . Post‐transcriptional transactivation of human retroviral envelope glycoprotein expression by herpes simplex virus US11 protein. Nature 1996;379:273-7.
    CrossRefMedline
  27. 27.↵
    1. Moriuchi M,
    2. Moriuchi H,
    3. Williams R,
    4. Straus SE
    . Herpes simplex virus infection induces replication of human immunodeficiency virus type 1. Virology 2000;278:534-40.
    CrossRefMedlineWeb of Science
  28. 28.↵
    1. Kucera LS,
    2. Leake E,
    3. Iyer N,
    4. Raben D,
    5. Myrvik QN
    . Human immunodeficiency virus type 1 (HIV‐1) and herpes simplex virus type 2 (HSV‐2) can coinfect and simultaneously replicate in the same human CD4+ cell: effect of coinfection of infectious HSV‐2 and HIV‐1 replication. AIDS Res Hum Retroviruses 1990;6:641-7.
    MedlineWeb of Science
  29. 29.↵
    1. Heng M,
    2. Heng S,
    3. Allen S
    . Co‐infection and synergy of human immunodeficiency virus–1 and herpes simplex virus–1. Lancet 1994;343:255-8.
    CrossRefMedlineWeb of Science
  30. 30.↵
    1. Schacker T,
    2. Ryncarz AJ,
    3. Goddard J,
    4. Diem K,
    5. Shaughnessy M,
    6. Corey L
    . Frequent recovery of HIV‐1 from genital herpes simplex virus lesions in HIV‐1‐infected men. JAMA 1998;280:61-6.
    Abstract/FREE Full Text
  31. 31.↵
    1. Augenbraun M,
    2. Corey L,
    3. Reichelderfer P,
    4. et al
    . The effect of herpes simplex virus shedding on plasma HIV RNA levels in coinfected women. Clin Infect Dis 2001;33:885-90.
    Abstract/FREE Full Text
  32. 32.↵
    1. Wald A,
    2. Zeh J,
    3. Selke S,
    4. Warren T,
    5. Ryncarz AJ,
    6. Ashley R,
    7. Krieger JN,
    8. Corey L
    . Reactivation of genital herpes simplex virus type 2 infection in asymptomatic HSV‐2 seropositive persons. N Engl J Med 2000;342:844-50.
    CrossRefMedlineWeb of Science
  33. 33.↵
    1. Wald A,
    2. Corey L,
    3. Cone R,
    4. Hobson A,
    5. Davis G,
    6. Zeh J
    . Frequent genital herpes simplex virus 2 shedding in immunocompetent women: effect of acyclovir treatment. J Clin Invest 1997;99:1092-7.
    MedlineWeb of Science
  34. 34.↵
    1. Schacker T,
    2. Zeh J,
    3. Hu HL,
    4. Hill E,
    5. Corey L
    . Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus‐infected men. J Infect Dis 1998;178:1616-22.
    Abstract/FREE Full Text
  35. 35.↵
    1. Hitti J,
    2. Watts DH,
    3. Burchett SK,
    4. et al
    . Herpes simplex virus seropositivity and reactivation at delivery among pregnant women infected with human immunodeficiency virus‐1. Amer J Obstet Gynecol 1997;177:450-4.
    CrossRefMedlineWeb of Science
  36. 36.↵
    1. Schacker T,
    2. Hu HL,
    3. Koelle DM,
    4. et al
    . Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV‐infected persons: a double‐blind, placebo‐controlled trial. Ann Intern Med 1998;128:21-8.
    Abstract/FREE Full Text
  37. 37.↵
    1. Wald A,
    2. Zeh J,
    3. Selke S,
    4. Ashley RL,
    5. Corey L
    . Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995;333:770-5.
    CrossRefMedlineWeb of Science
  38. 38.↵
    1. Collier AC,
    2. Coombs RW,
    3. Schoenfeld DA,
    4. et al
    . Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 1996;334:1011-7.
    CrossRefMedlineWeb of Science
  39. 39.↵
    1. Boeckh M,
    2. Boivin G
    . Quantitation of cytomegalovirus: methodologic aspects and clinical application. Clin Microbiol Rev 1998;11:533-54.
    Abstract/FREE Full Text
  40. 40.↵
    1. Lipsitz SR,
    2. Dear KB,
    3. Zhao L
    . Jackknife estimators of variance for parameter estimates from estimating equations with applications to clustered survival data. Biometrics 1994;50:842-6.
  41. 41.↵
    1. Mole L,
    2. Ripich S,
    3. Margolis D,
    4. Holodnyi M
    . The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 1997;176:766-70.
    Abstract/FREE Full Text
  42. 42.↵
    1. Mellors JW,
    2. Rinaldo CR Jr.,
    3. Gupta P,
    4. et al
    . Prognosis in HIV‐1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167-70.
    Abstract
  43. 43.↵
    1. Centers for Disease Control and Prevention
    . Sexually transmitted disease guidelines 2002. MMWR Recomm Rep 2002;52:1-78.
  44. 44.↵
    1. Palella FJ,
    2. Delaney KM,
    3. Moorman AC,
    4. et al
    . Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:906-8.
    CrossRefMedlineWeb of Science
  45. 45.↵
    1. Benedetti JK,
    2. Zeh J,
    3. Corey L
    . Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 1999;131:14-20.
    Abstract/FREE Full Text
| Table of Contents

This Article

  1. J Infect Dis. (2002) 186 (12): 1718-1725. doi: 10.1086/345771
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 205 (5)
  1. Journal of Infectious Diseases
  1. Alert me to new issues

Most